This invention relates to the treatment of alcoholism and particularly to an extinction method of treating alcoholism using a transdermally administered opiate antagonist. The invention also relates to a device for the rapid, transdermal administration or delivery of a fixed dose of the opiate antagonist.
A method for treating alcoholism by extinguishing the alcohol-drinking response is described in copending United States patent application Ser. No. 205,758, the disclosure of which is incorporated herein in its entirety by reference. In this extinction method, an opiate antagonist is administered to a subject suffering from alcoholism in a daily dosage sufficient to block the stimulatory effect of alcohol and, while the amount of antagonist in the subject's body is sufficient to block the stimulatory effect of alcohol, the subject is made to drink an alcoholic beverage. The steps of administration of the opiate antagonist and drinking of an alcoholic beverage are continued until the alcohol-drinking response is extinguished.
Existing methods for administering opiate antagonists, however, are inadequate for use in the extinction of the alcohol-drinking response.
Injection produces a strong stimulus which, together with any lingering irritation, would clearly distinguish the extinction sessions from normal alcohol drinking. The presence of such stimuli are known to interfere with the process of extinction (David W.M. and Smith, S.G. Biological Psychiatry 9: 181-189, 1974). Injection also reduces motivation and the willingness of the patient to remain in the treatment, which is an important consideration in alcoholism treatment.
Oral administration has the problem that compliance is difficult to assure, whereas it is essential in the extinction process that the alcoholic actually takes the antagonist before each session. Furthermore, oral administration currently can only be used with the antagonist naltrexone, and naltrexone has two disadvantages. First, it is a major liver toxin, which excludes it being used with many alcoholics. Second, it has such a long half-life in the body that there would still be active quantities present long after the end of a session. In order to avoid extinction of responses other than alcohol drinking, and to allow the other responses that are weakened during a session to regain their strength between sessions, it is desirable to restrict the presence of the antagonist as much as possible to the sessions, i.e., to the few hours in a day when the alcoholic is permitted to drink alcohol. Consequently, both a low build up of the antagonist in the body before a session and its continued presence after the session should be avoided as much as possible.
Transdermal administration can avoid these problems. It is painless and produces no clear stimulus provided that transdermal patches are not needed. Compliance is easy to monitor. Moreover, such administration can deliver naloxone which has a desirably short half-life for use in extinction. Transdermal devices previously disclosed for administering opiate antagonists, however, are not suitable for use in alcoholics for extinguishing the alcohol-drinking response.
All but one of the transdermal devices disclosed for administering opiate antagonists are patches. The presence of a patch would likely act as a stimulus present during the extinction sessions distinguishing them from normal drinking, and thus reducing the effectiveness of the extinction process. Furthermore, the disclosed transdermal patches do not generally provide sufficiently rapid delivery for use in the extinction procedure.
Three of the transdermal devices for opiate antagonists (Gale et al, U.S. Pat. No. 4,645,502, issued Feb. 24, 1987; Leeson, U.S. Pat. No. 4,680,172, issued July 14, 1987; and Chien et al, U.S. Pat. No. 4,806,341, issued Feb. 21, 1989, and related patents in other countries) are "system controlled" transdermal patches. That is, the patches contain a mechanism restricting and controlling the rate at which the antagonist is delivered. This prevents an initially high rate of delivery when the patch is first applied and allows long-term, sustained delivery at a relatively steady rate.
System-controlled devices are superior for most uses. For example, such devices would be preferred in the previously envisioned use of opiate antagonists to prevent the taking of narcotics (see NIDA Research Monograph No. 28, 1982). It was hypothesized that if addicts could be kept continually on an opiate antagonist, which blocks the pleasure from narcotics, the addicts would behave rationally and refrain from taking narcotics. Consequently, much work was done to try to find sustained delivery methods for antagonists that would supply constant amounts for very long periods of time. Sustained release is, however, neither necessary nor preferable for the delivery of antagonists in the extinction procedures. Because of the relatively wide therapeutic window, it is not necessary to keep the delivery rate constant. The added mechanisms in these devices to control the delivery rate, in addition to making them more complicated and expensive than necessary for use in the extinction procedure, also cause the time required to build up active quantities of antagonist to be unacceptably long and preclude delivery of the highest doses specified for the extinction procedure (e.g., 30 mg of naloxone.)
The device disclosed by Gale et al, U.S. Pat. No. 4,645,502, has only 30 .mu.g/cm.sup.2 /hr as the highest mentioned delivery rate, are fabricated in sizes up to only 40 cm.sup.2 (thus giving a maximum delivery rate of 1.2 mg/hr), and has a lag time of 2-7 hours. The device disclosed by Leeson, U.S. Pat. No. 4,680,172, administers naloxone "at a rate of 0.01 to 5 mg/hr, preferably 0.02 to 2 mg/hr." Chien et al, U.S. Pat. No. 4,806,341, disclose no information about the rates for delivery of naloxone or other antagonists. The maximum rates shown for hydromorphone, up to about 100 .mu.g/cm.sup.2 /hr approach those needed for naloxone in the extinction procedure if a sufficiently large patch is used, but the only size mentioned, 10 cm.sup.2, would deliver only 1 mg/hr. In contrast a device for use in the extinction procedure should be capable of delivering a minimum of 6 mg and, preferably, 9 mg or more of an opiate angatonist in an hour.
Two other transdermal patch devices have been disclosed that are "skin-controlled", i.e., they do not have an added mechanism for restricting delivery, but they also do not provide a rate of delivery high enough to be used in the extinction procedure. Maeth et al, U.S. Pat. No. 3,249,109, issued May 3, 1966, discloses a topical dressing for applying medicaments or therapeutic agents through the skin. The patent, however, does not suggest the use of any permeation enhancer, i.e., a substance to increase the rate of diffusion of the drug across the skin. In the absence of such enhancers, the absorption of naloxone or naltrexone is not sufficient for systemic delivery of therapeutic doses.
Cheng et al, U.S. Pat. No. 4,573,995, issued Mar. 4, 1986, discloses a transdermal patch for the bases of naloxone and related drugs, with the permeation enhancer polyethylene glycol monolaurate. The highest mentioned flux was only 30.58 .mu.g/cm.sup.2 /hr, although rates of up to 40 .mu.g/cm.sup.2 /hr are claimed.
Another transdermal means for delivering opiate antagonists is disclosed in Aungst et al, U.S. Pat. No. 4,626,539, issued Dec. 2, 1986. Vehicles and enhancers capable of delivering opiate antagonists at rates sufficient for use in the extinction procedure, e.g., several combinations produce rates for naloxone of over 300 .mu.g/cm.sup.2 /hr, are described. A transdermal patch is mentioned. The preferred means, however, are lotions and creams. These means are inadequate for use by alcoholics because of the difficulty in controlling the total dose applied. The dose could be determined by squeezing a cylinder of a specified length out of a tube, as is done, e.g., with the transdermal delivery of nitroglycerin. This method, however, would not be appropriate for an alcoholic to self-administer an antagonist: unless there was very strict supervision, the risk of underdosing or overdosing would be too high. Most alcoholism treatment centers do not have sufficient staff for such strict supervision. For these centers and to simplify the procedure for use in all centers, it is necessary to have a device that reliably delivers a fixed dose of the antagonist. The device should be simple to use, as foolproof as possible, and inexpensive to manufacture.